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1. Serotonin
Serotonin (5-hydroxytryptamine; 5-HT), named by Rapport et al. (1948) [1], is one of the ubiquitous molecules acting as messengers, well known as a neurotransmitter and neuromodulator. Serotonin (Figure 1) is mostly found outside the central nervous system [2]; it was first identified in enterochromaffin cells and named as “enteramine” by Vialli and Erspamer in 1937 and confirmed to be the same entity with the “clotted blood” vasoconstriction effects in 1952 [3].
[figure omitted; refer to PDF]2. Serotonin as an Ancient Molecular Signal
The serotonergic system is an ancient sensor of diverse stimuli and molecular signaling in single-celled eukaryotes, plants, and animals [4–6].
The regulated expression of genetic material in every cell is very important and a “regulatory lesson” learned over the years is that small metabolites are often regulatory signals to control gene expression. For “expensive” biosynthesis, as the required for the serotonin precursor tryptophan, common pathways are found in organisms that take advantage of the aromatic structures; tryptophan serves as the precursor not only of serotonin (Figure 2), but also of very important compounds as niacin in eukaryotes, indoleacetic acid in plants, and indole in bacteria. Regulatory strategies could be compatible with other metabolic goals as organisms evolved capable of obtaining tryptophan by feeding, with specific plasma membrane transporters [7, 8].
[figure omitted; refer to PDF]Beyond the heterotrophic theory of the very first living organisms [9], serotonin could be used as specific signal, after direct relation with tryptophan synthesis was controlled, and specific monoamine transporters that do not need the missing carboxyl group of the aminoacids [7, 10] were present; later, it acquired functions of “hormone” and growth factor, and serotonin activity as neurotransmitter was achieved at last [4]. In prenervous stages, serotonin regulates basic developmental processes from cleavage divisions after fertilization (proliferator) to morphogenetic cell movements during gastrulation (morphogen) in sea urchin [11]. Presence of serotonin and its metabolite 5-hydroxyindoleacetic acid in unicellular ciliate Tetrahymena pyriformis [12] and increasing RNA production in the 5-HT stimulated protozoa [13] suggested an active biogenic amine system with relevant functions; interaction with GTPases might represent some of the earlier functions of serotonin (and biogenic amines) before it could be vesiculated and its exocytosis could be regulated for metazoan serotonergic systems [14, 15].
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